Rucaparib Monotherapy Improves Radiographic Progression-Free Survival in Patients With Metastatic Castration-Resistant Prostate Cancer: TRITON3 Trial - Alan Bryce
December 20, 2022
In this conversation, Alicia Morgans and Alan Bryce highlighted the TRITON3 study. TRITON3 is a Phase 3, multicenter, open-label, randomized trial of Rubraca in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). The study enrolled 405 patients with a mutation in BRCA or ATM who were randomized to Rubraca or the control group, which consisted of the physician’s choice of docetaxel, abiraterone acetate, or enzalutamide. Rucaparib had accelerated approval from the FDA based upon the TRITON2 data, which tested Rucaparib in the post-docetaxel setting after at least one androgen pathway inhibitor.
TRITON3 is the follow on study with a slightly different design. It is a 2:1 randomization of rucaparib versus the physician's choice in the pre-docetaxel setting. All the patients going on to the study had received at least one androgen pathway inhibitor. They didn't receive any taxane for castration-resistant disease, although they were allowed to have received it for hormone-sensitive disease. The take-home message in this conversation is that this is a positive study showing the superiority of rucaparib over physician's choice in the select population.
Biographies:
Alan H. Bryce, MD, Medical Director of the Genomic Oncology Clinic at Mayo Clinic, Arizona
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
TRITON3 is the follow on study with a slightly different design. It is a 2:1 randomization of rucaparib versus the physician's choice in the pre-docetaxel setting. All the patients going on to the study had received at least one androgen pathway inhibitor. They didn't receive any taxane for castration-resistant disease, although they were allowed to have received it for hormone-sensitive disease. The take-home message in this conversation is that this is a positive study showing the superiority of rucaparib over physician's choice in the select population.
Biographies:
Alan H. Bryce, MD, Medical Director of the Genomic Oncology Clinic at Mayo Clinic, Arizona
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Related Content:
TRITON3 Phase 3 Trial Of Rubraca® (Rucaparib) Achieves Primary Endpoint In Men With Metastatic Castration-Resistant Prostate Cancer With BRCA or ATM Mutations
The Current Landscape of Metastatic Castration-Resistant Prostate Cancer: Immunotherapy and Targeted Therapies
The Modifiers That Impact Response to the PARP Inhibitor Rucaparib from TRITON2 - Wassim Abida
TRITON3 Phase 3 Trial Of Rubraca® (Rucaparib) Achieves Primary Endpoint In Men With Metastatic Castration-Resistant Prostate Cancer With BRCA or ATM Mutations
The Current Landscape of Metastatic Castration-Resistant Prostate Cancer: Immunotherapy and Targeted Therapies
The Modifiers That Impact Response to the PARP Inhibitor Rucaparib from TRITON2 - Wassim Abida
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here with Dr. Alan Bryce, who is visiting with us to talk about the TRITON3 trial. Thank you so much for joining me today.
Alan Bryce: Thanks for having me. It's a pleasure to be here.
Alicia Morgans: It is a pleasure to talk to you and so exciting to really dig into some of the TRITON3 data. Of course, early days, not everything is released.
Alan Bryce: Yeah.
Alicia Morgans: And we are expecting to hear more in the future. Can you set us up by just telling us what was the design of this study?
Alan Bryce: Yeah, so TRITON3 is testing Rucaparib for patients with prostate cancer that carry mutations in either BRCA one, two, or ATM. Remember that Rucaparib had accelerated approval from the FDA based upon the TRITON2 data, which tested Rucaparib in the post-Docetaxel setting after at least one androgen pathway inhibitor. In this era it was Abiraterone or Enzalutamide.
TRITON3 is the then mandated follow on study with a slightly different design because it's a randomized trial, two to one randomization of Rucaparib versus physician's choice in the pre-Docetaxel setting. All the patients going on to the study had received at least one androgen pathway inhibitor. They didn't receive any taxane for castration resistant disease, although they were allowed to have received it for hormone sensitive disease.
I think what's very relevant in the study design is this randomization where patients got either Rucaparib, or in the physician's choice, the physician could choose between Docetaxel or Abiraterone or Enza, whichever one of the two oral agents they hadn't received before.
And so this was a very rigorous design, somewhat of a reach, if you will, because we all know that Docetaxel is the really active drug after one androgen pathway inhibitor. And most prior studies had always randomized against the oral agents. But to the credit of the investigators and Clovis, the company, they really insisted that we were going to have the active comparator that we felt was most appropriate in Docetaxel.
It was a randomized clinical trial, two cohorts, the core cohort of 300 patients with BRCA aberrant disease, and then an extra 100 patients were included with ATM mutant disease, which was the greater intention to treat cohort.
Alicia Morgans: Wonderful. And we've certainly seen a press release.
Alan Bryce: Yeah.
Alicia Morgans: But I'd love to hear the high level of results, whatever you're allowed to share with us.
Alan Bryce: Yeah. The top line data is that this is a positive study for radiographic progression free survival favoring rucaparib over the physician's choice. And I think this is tremendously exciting that we have a clinical trial now where any drug actually beat docetaxel, and mCRCP. It's the first time we've seen this. You and I have been doing this a long time and we've seen a lot of drugs come and go in this space. No surprise though that a PARP inhibitor is better than the physician's choice for the BRCA select population. It's a very nice result. It's exactly what one would expect. The results were in line actually with the study design. This will be the basis for a submission to the FDA for an expanded label indication and to move beyond the accelerated approval to a full approval.
Alicia Morgans: Well, I think we should really importantly stress what you just said, which is that this study was the first to really randomize the treatment arm against Docetaxel for those patients who received it. Now, remember, as you said also, it's physician's choice.
Alan Bryce: Yeah.
Alicia Morgans: So not every patient received Docetaxel, but a very highly active control arm, which is different than the other drugs that have been approved in the space. Very, very interesting.
Alan Bryce: Yeah.
Alicia Morgans: And really exciting and may give us the opportunity to potentially use Rucaparib in a pre-Docetaxel space should that regulatory approval come through after the review process.
Alan Bryce: Yeah.
Alicia Morgans: Very, very interesting.
Now, I wonder, were there new safety signals identified here that were not seen in TRITON2? Where of course we already have the approval, we've been using this drug in practice, so we have some sense, I think, as a community about the Rucaparib adverse events.
Alan Bryce: Yeah, so fortunately, no, no new safety signals at all. Everything was in line with what was seen in TRITON2, also in line with what's been seen in the breast and ovarian cancer studies. I think at one point there was a question of should PARP inhibitors have different toxicity in men versus women, just because we didn't know, but no, there's no difference that we can see. No surprises on the safety. Rucaparib's been used in a lot of patients already so it'll be very familiar, I think, for everybody.
Alicia Morgans: Okay, well, that's exciting.
If you had to give us a summary, what would that summary and message be about TRITON3? And remember, we are planning to and expecting to see more data.
Alan Bryce: Yes.
Alicia Morgans: In the near future, I hope, but what's the highlight that we should take home?
Alan Bryce: Yeah.
Yes, this is early days. You will see more data coming out. This was the first release here at PCF but more complete data coming forward.
The take home is that this is a positive study. This is a positive study showing the superiority of Rucaparib over physician's choice in the select population. That it is well tolerated with no big surprises, no untoward side effects that we weren't anticipating. Of course, the FDA will adjudicate, but I think we can really take a tremendous amount of joy, I hope, in the fact that we've shown that something is superior to Docetaxel in this space.
I also anticipate that we'll eventually be able to give the breakdown of the response by the comparator drug. The fact of the matter is that Docetaxel was a majority of the patients and that's really going to allow us, I think, to help the clinician tell the patient why Rucaparib is better than the most appropriate alternative choice, which would be chemotherapy. Really, I think, a robust data set that's going to help clinicians in the clinic and something that's going to expand the armamentarium for patients as we try to sort out this kind of complicated mCRPC space.
Alicia Morgans: Wonderful. Well, thank you so much for your time today and certainly congratulations to you, the investigators, and all of the patients who participated. We really appreciate your efforts and your time today.
Alan Bryce: Thanks. Thanks for having us.
Alicia Morgans: Hi, I'm so excited to be here with Dr. Alan Bryce, who is visiting with us to talk about the TRITON3 trial. Thank you so much for joining me today.
Alan Bryce: Thanks for having me. It's a pleasure to be here.
Alicia Morgans: It is a pleasure to talk to you and so exciting to really dig into some of the TRITON3 data. Of course, early days, not everything is released.
Alan Bryce: Yeah.
Alicia Morgans: And we are expecting to hear more in the future. Can you set us up by just telling us what was the design of this study?
Alan Bryce: Yeah, so TRITON3 is testing Rucaparib for patients with prostate cancer that carry mutations in either BRCA one, two, or ATM. Remember that Rucaparib had accelerated approval from the FDA based upon the TRITON2 data, which tested Rucaparib in the post-Docetaxel setting after at least one androgen pathway inhibitor. In this era it was Abiraterone or Enzalutamide.
TRITON3 is the then mandated follow on study with a slightly different design because it's a randomized trial, two to one randomization of Rucaparib versus physician's choice in the pre-Docetaxel setting. All the patients going on to the study had received at least one androgen pathway inhibitor. They didn't receive any taxane for castration resistant disease, although they were allowed to have received it for hormone sensitive disease.
I think what's very relevant in the study design is this randomization where patients got either Rucaparib, or in the physician's choice, the physician could choose between Docetaxel or Abiraterone or Enza, whichever one of the two oral agents they hadn't received before.
And so this was a very rigorous design, somewhat of a reach, if you will, because we all know that Docetaxel is the really active drug after one androgen pathway inhibitor. And most prior studies had always randomized against the oral agents. But to the credit of the investigators and Clovis, the company, they really insisted that we were going to have the active comparator that we felt was most appropriate in Docetaxel.
It was a randomized clinical trial, two cohorts, the core cohort of 300 patients with BRCA aberrant disease, and then an extra 100 patients were included with ATM mutant disease, which was the greater intention to treat cohort.
Alicia Morgans: Wonderful. And we've certainly seen a press release.
Alan Bryce: Yeah.
Alicia Morgans: But I'd love to hear the high level of results, whatever you're allowed to share with us.
Alan Bryce: Yeah. The top line data is that this is a positive study for radiographic progression free survival favoring rucaparib over the physician's choice. And I think this is tremendously exciting that we have a clinical trial now where any drug actually beat docetaxel, and mCRCP. It's the first time we've seen this. You and I have been doing this a long time and we've seen a lot of drugs come and go in this space. No surprise though that a PARP inhibitor is better than the physician's choice for the BRCA select population. It's a very nice result. It's exactly what one would expect. The results were in line actually with the study design. This will be the basis for a submission to the FDA for an expanded label indication and to move beyond the accelerated approval to a full approval.
Alicia Morgans: Well, I think we should really importantly stress what you just said, which is that this study was the first to really randomize the treatment arm against Docetaxel for those patients who received it. Now, remember, as you said also, it's physician's choice.
Alan Bryce: Yeah.
Alicia Morgans: So not every patient received Docetaxel, but a very highly active control arm, which is different than the other drugs that have been approved in the space. Very, very interesting.
Alan Bryce: Yeah.
Alicia Morgans: And really exciting and may give us the opportunity to potentially use Rucaparib in a pre-Docetaxel space should that regulatory approval come through after the review process.
Alan Bryce: Yeah.
Alicia Morgans: Very, very interesting.
Now, I wonder, were there new safety signals identified here that were not seen in TRITON2? Where of course we already have the approval, we've been using this drug in practice, so we have some sense, I think, as a community about the Rucaparib adverse events.
Alan Bryce: Yeah, so fortunately, no, no new safety signals at all. Everything was in line with what was seen in TRITON2, also in line with what's been seen in the breast and ovarian cancer studies. I think at one point there was a question of should PARP inhibitors have different toxicity in men versus women, just because we didn't know, but no, there's no difference that we can see. No surprises on the safety. Rucaparib's been used in a lot of patients already so it'll be very familiar, I think, for everybody.
Alicia Morgans: Okay, well, that's exciting.
If you had to give us a summary, what would that summary and message be about TRITON3? And remember, we are planning to and expecting to see more data.
Alan Bryce: Yes.
Alicia Morgans: In the near future, I hope, but what's the highlight that we should take home?
Alan Bryce: Yeah.
Yes, this is early days. You will see more data coming out. This was the first release here at PCF but more complete data coming forward.
The take home is that this is a positive study. This is a positive study showing the superiority of Rucaparib over physician's choice in the select population. That it is well tolerated with no big surprises, no untoward side effects that we weren't anticipating. Of course, the FDA will adjudicate, but I think we can really take a tremendous amount of joy, I hope, in the fact that we've shown that something is superior to Docetaxel in this space.
I also anticipate that we'll eventually be able to give the breakdown of the response by the comparator drug. The fact of the matter is that Docetaxel was a majority of the patients and that's really going to allow us, I think, to help the clinician tell the patient why Rucaparib is better than the most appropriate alternative choice, which would be chemotherapy. Really, I think, a robust data set that's going to help clinicians in the clinic and something that's going to expand the armamentarium for patients as we try to sort out this kind of complicated mCRPC space.
Alicia Morgans: Wonderful. Well, thank you so much for your time today and certainly congratulations to you, the investigators, and all of the patients who participated. We really appreciate your efforts and your time today.
Alan Bryce: Thanks. Thanks for having us.